Chirospecific and subtype selective dopamine receptor binding of heterocyclic methoxynaphthamide analogs

Employing the D(3) and D(4) selective methoxynaphthalines nafadotride and FAUC 182, respectively, as lead compounds, the pyrazolo[1,5-a]pyridine-3-carboxamides of type 1a and 2a as well as their 2-substituted regioisomers 1b and 2b were synthesized when following an ex-chiral pool approach. Dopamine receptor binding studies involving the target compounds (1a,b, 2a,b) and the respective optical antipodes ent-1a,b and ent-2a,b revealed the heterocyclic carboxamide 2a as a strong and selective D(4) ligand (K(i) = 8.6 nM). According to a mitogenesis assay, 2a shows D(4) partial agonist effects (29%, EC(50) = 6.7 nM) and, thus, might be of interest for the treatment of sexual dysfunction.